Dolastatin 15 is a cytostatic depsipeptide isolated from the marine mollusk Dolabella auricularia by Pettit et. al. in 1989. Among the dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cytostatic peptide isolated from the Indian Ocean sea hare, dolastatin 15 as well as dolastatin 10 represent the two most important members because of the strong and selective activities.For completing the synthesis of dolastatin 15, single step segment condensation between peptide fragment and nonpeptide fragment by the CIP/HOAt method was used, since activation at the Pro residue is resistance to isomerization. N, N-dimethylamino acid was incorporated in peptide fragment 2 since CIP-mediated activation is expected to be efficient enough for hindered couplings in solution. Pro, 2-hydroxyisovaleric acid (Hiva), and Phe was employed for the preparation of nonpeptide fragment. The Pyrrolidone ring of was constructed by the CIP-mediated coupling of Phe and Meldrum's ester emplo
… Moreyed as C2 unit. For the preparation of peptide fragment, CIP-mediated activation for the coupling of N-methylamino acid on solid support was selected as a preferable scheme to facilitate the practical synthesis of dolastatin 15. Thus, prior to the synthesis of dolastatin 15 according to the scheme, we evaluated CIP-mediated activation for its efficiency in preparing peptide sequence containing N-methylamino acids on solid support.In conclusion, a convergent synthesis utilizing single step condensation of fragment and pyrrolidone fragment using CIP-HOAt as an efficient coupling reagent was achieved. The CIP-mediated reaction was also successfully applied for coupling of N-methylamino acid on solid support, demonstrating the first practical application of the solid-phase procedure for natural product synthesis最後に、両成分の縮合をCIP/HOAt法により行ない、ドラスタチン15を得た。この一段階縮合反応は、ドラスタチン15の構造決定を行なったPettitらが当初試みた合成経路であるが、縮合効率が上がらなかったため断念した方法である。構造活性相関:各構成アミノ酸の疎水性、親水性のバランスを考慮しつつアミノ酸の置換を行なうため、固相上縮合反応における反応ユニットの置換を行って誘導体の合成を行った。 Less